title: New coumarin-based anti-inflammatory drug: putative antagonist of the integrins alphaLbeta2 and alphaMbeta2.
abstract: This study was conducted to investigate putative antagonism of integrin receptors alphaMbeta2 and alphaLbeta2 by a novel coumarin derivative (BOL-303225-A), its efficacy in-vivo after retinal ischaemia-reperfusion injury, and its bioavailability in rat plasma. A cellular adhesion assay in Jurkat and U937 cells, and a flow cytometry assay with an antibody against the beta2 subunit were conducted. BOL-303225-A bioavailability in rat plasma and the retinal levels of myeloperoxidase (MPO) after ischaemia-reperfusion injury were evaluated after oral administration (10 mg kg(-1)). In-vitro cell viability assays revealed no cytotoxicity for BOL-303225-A over a wide dose range, and IC50 values of 32.3 +/- 1.5 muM and 84.95 +/- 2.3 muM were found for Jurkat and U937 cells, respectively. The drug showed specific binding to the alphaMbeta2 and alphaLbeta2 integrin receptors expressed by U937 and Jurkat cells, respectively, producing a fluorescence shift towards lower values in a concentration-dependent manner. The pharmacokinetic profile of BOL-303225-A exhibited rapid absorption following oral administration in the rat. A significant reduction of retinal MPO levels was observed in drug-treated rats. This study demonstrated that BOL-303225-A acts as an antagonist of the integrin alphaLbeta2 and alphaMbeta2 receptors, suggesting that this drug could be used for ocular diseases such as diabetic retinopathy.
authors.affiliation: Department of Experimental and Clinical Pharmacology, School of Medicine, University of Catania, Catania, Italy. bucocla@unict.it
authors.forename: Claudio
authors.initials: C
authors.lastname: Bucolo
authors.forename: Adriana
authors.initials: A
authors.lastname: Maltese
authors.forename: Francesco
authors.initials: F
authors.lastname: Maugeri
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.forename: Monica
authors.initials: M
authors.lastname: Baiula
authors.forename: Antonino
authors.initials: A
authors.lastname: Spartà
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects* / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D012164:Retinal Diseases / Q000188:drug therapy / Q000473:pathology; D020298:U937 Cells
chemical_list: D000893:Anti-Inflammatory Agents; C520526:BOL-303225-A; D003374:Coumarins; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D009195:Peroxidase